Application and allergic reaction of methylhexahydrophthalic anhydride

Introduction

Methylhexahydrophthalic anhydride (Figure.1) is a reactive, low molecular weight chemical used in products such as plastics, paints, and electronic components. In the body, Methylhexahydrophthalic anhydride is hydrolyzed to methylhexahydrophthalic acid (MHHP acid), and methods for biologicalmonitoring of methylhexahydrophthalic anhydride using MHHP acid in urine have beendescribed by Lindh et al.. There is a close correlation between air levels of methylhexahydrophthalic anhydride and urinary creatinine-adjusted levels of MHHP acid. In addition, methylhexahydrophthalic anhydride reacts and forms adducts with endogenous proteins, e.g. hemoglobin (Hb) and human serum albumin (HSA). It has been shown that the MHHPA adducts of the plasma proteins are highly suitable biomarkers of long-term exposure to methylhexahydrophthalic anhydride. An interesting observation is that MHHPA seems to form three times more adducts at the same air levels than does HHPA.[1]

Methylhexahydrophthalic anhydride (MHHPA) in electric industry

Methylhexahydrophthalic anhydride (MHHPA) is a hardener for hot-cured epoxy resins employed as insulators in the electric industry. MHHPA has only been measured as an ingredient with other alicyclic anhydrides, albeit there are also large processes which use only MHHPA. We collected MHHPA vapour in a set of devices: Teflon filter, glass spiral, TenaxTA tube connected consecutively together. Elution was performed with a solvent mixture of methyl-tert-butyl ether (70%), acetonitrile (30%), and acetic anhydride (0.5%). By capillary GC-ECD, the regression was linear (0.9994) in the practical low concentration range of 0.04-1 microg/ml being equal to 0.001-0.035mg/m³ in 30 l of air. The exposure was measured in two factories manufacturing electric appliances. The assembled objects were first impregnated with a liquid epoxy/hardener mixture, and then the resin hardened at elevated temperature. In condenser manufacturing, the operators' 8 h exposure ranged from 0.068 to 0.118 mg/m³, and the short-term exposure was during operation at ovens mean 1.90 mg/m³. The impregnation of coiled resistors and transfer of them to ovens caused the worst exposures, short-term mean 3.846 mg/m³ and long-term mean 2.191 mg/m³. During the 'baking', the ovens were closed and evacuated, but when the hot objects were moved out of the ovens, they continued during chilling to emit MHHPA, mean 0.366mg/m³. In the adjacent areas, assembling, control rooms, offices, the exposure was still significant, 0.017-0.043 mg/m³, due to leaks from the high exposure areas. Mechanical general ventilation and local exhausts were functioning. Respirators were available for short supervising of the hot equipment.[2]

TPPA levels of HHPA and MHHPA as biomarkers of long-term exposure to anhydrides

The aim of this study was to evaluate the applicability of total plasma protein adducts (TPPA) of 2 sensitizing low-molecular-weight allergens, hexahydrophthalic anhydride (HHPA) and methylhexahydrophthalic anhydride (MHHPA), as biomarkers of long-term exposure. Urine samples from occupationally exposed workers were analyzed for the levels of urinary metabolites of HHPA and methylhexahydrophthalic anhydride, and the levels were used as the index of exposure. In addition, blood samples were obtained from the same persons, and the levels of TPPA were determined. Reversed solid phase extraction, derivatization using pentafluorobenzyl bromide, and gas chromatography-mass spectrometry analysis in the negative ion chemical ionization mode were used to quantify the exposure. To assess the suitability of TPPA as a biomarker of exposure to the anhydrides, the TPPA levels were correlated to urinary metabolite levels and hemoglobin (Hb) adducts. The toxicokinetics of TPPA were also studied to determine the elimination half-time of the adducts. The levels of TPPA correlated exceptionally well with the metabolite levels in the urine sampled repeatedly, giving r=0.97 for HHPA and r=0.92 for methylhexahydrophthalic anhydride. The TPPA of HHPA correlated highly with the Hb adducts with r=0.86. There were also good correlations between single urinary determinations and the TPPA levels (r(s)=0.71 and 0.81, respectively, for HHPA and methylhexahydrophthalic anhydride). The in vivo decay of TPPA gave an elimination half-time of 22 days for HHPA and 24 days for methylhexahydrophthalic anhydride.TPPA levels of HHPA and methylhexahydrophthalic anhydride are excellent biomarkers of long-term exposure to anhydrides.[3]

Allergic reaction of methylhexahydrophthalic anhydride

Methylhexahydrophthalic anhydride in nasal lavage fluid

Exposure to methylhexahydrophthalic anhydride may lead to work-related airway diseases such as rhinitis, conjunctivitis, and asthma. Twelve subjects employed at a plant manufacturing electrical capacitors using methylhexahydrophthalic anhydride were included in this study. Nasal lavages were collected from subjects before work Monday morning and after work Tuesday afternoon. The levels of methylhexahydrophthalic anhydride adducted to serum albumin were analyzed with a straightforward work-up method. The samples were trypsinated before being analyzed with a liquid chromatography-triple quadrupole mass spectrometer. The mass spectrometer was run using selected reaction monitoring for six adducted peptides. Also, some biomarkers of effect (albumin, total protein, eosinophil cationic protein, and tryptase) were analyzed in nasal lavages. Furthermore, the metabolite MHHP acid in urine after work on Tuesday was analyzed by gas chromatography-mass spectrometry. Symptoms from the airways and the eyes and sensitization were registered. The main result of this study is that protein adducts can be analyzed in vivo after low occupational exposures to methylhexahydrophthalic anhydride . The results also show a correlation between adducted peptides and albumin in nasal lavage. Furthermore, there may be a difference in the potential to induce hyperresponsiveness between adducts bound to different amino acids.[1]

Delayed and immediate allergy

Epoxy resin compounds (ERC) include a large number of chemicals, such as epoxy resins (ER), reactive diluents and hardeners. Many hardeners, e.g., aliphatic polyamines, are well-known sensitizers. Another type of ER hardeners are the phthalic anhydrides, such as methylhexahydrophthalic anhydride (MHHPA) and methyltetrahydrophthalic anhydride (MTHPA), which have been reported as causing immunologically-mediated respiratory diseases and contact urticaria, but not allergic contact dermatitis. Here, researchers present a horizontal boring-machine worker who developed allergic contact dermatitis, as well as allergic rhinitis and an immediate contact skin reaction from methylhexahydrophthalic anhydride. Patch testing with a dilution series of MHHPA in pet. elicited the following results: 2%, 1% and 0.5%, +2; 0.25% and 0.125%, + (3- to 6-day readings). An immunohistochemical and electron microscopic study also indicated that the patch test reactions were conventional-delayed allergic reactions. Interleukin 8 was observed in the epidermal cells, whereas interleukin 4 immunoreactivity was detected in the dermal cells. Immunoreactivity to-interleukin 5, granulocyte/macrophage-colophony stimulating factor (GM-CSF) or eosinophil cationic protein was not seen. In conclusion, the patient developed both Type I and Type IV allergy to MHHPA. The clinical data, patch test results, immunohistochemical and electron microscopic observations indicated that the MHHPA allergy detected by the patch test reaction was a conventional delayed-type hypersensitivity reaction. The patient also had an allergic patch test reaction to para-phenylenediamine and diaminodiphenylmethane, possibly representing occupational sensitization.[4]

Occupational contact urticaria

Acid anhydrides are low-molecular weight chemicals known to cause respiratory irritancy and allergy. Skin allergy has on rare occasions been reported. A total of 3 subjects with occupational exposure to methylhexahydrophthalic anhydride (MHHPA) and hexahydrophthalic anhydride (HHPA) from an epoxy resin system were studied to evaluate the nature of their reported skin and nose complaints (work-related anamnesis, specific IgE, contact urticaria examinations, and ambient monitoring). Using a Pharmacia CAP system with a HHPA human serum albumin conjugate, specific IgE antibody was detected in serum from 1 (33.3%) out of the 3 workers. One unsensitized worker displayed nasal pain and rhinorrhea only when loading liquid epoxy resins into the pouring-machine (2.2mg MHHPA/m³ and 1.2mg HHPA/m³), probably being an irritant reaction. Two workers had work-related symptoms at relatively low levels of exposure (geometric mean 32-103 microg methylhexahydrophthalic anhydride/m³ and 18-59 microg HHPA/m³); one complained of only rhinitis, and the other was sensitized against HHPA and displayed both rhinitis and contact urticaria (the face and neck). The worker's skin symptoms were evidently due to airborne contact, since she had not had any skin contact with liquid epoxy resin or mixtures of methylhexahydrophthalic anhydride and HHPA. These urticaria symptoms were confirmed by a 20-min closed patch test for methylhexahydrophthalic anhydride, but not by that for HHPA. The causative agent was considered to be MHHPA, although the specific IgE determination to methylhexahydrophthalic anhydride was not performed.[5]

References

1.Jeppsson MC, Lindh CH, Kristiansson MH, Nielsen J, Jönsson BA. Methylhexahydrophthalic anhydride adducted albumin tryptic peptides in nasal lavage fluid. Inhal Toxicol. 2009;21(12):1013-1020. doi:10.1080/08958370802715997

2.Pfäffli P, Hämeilä M, Riala R, Tornaeus J, Wirmoila R. Exposure to methylhexahydrophthalic anhydride (MHHPA) in two workplaces of the electric industry. J Environ Monit. 2004;6(4):295-299. doi:10.1039/b310964j

3.Rosqvist S, Johannesson G, Lindh CH, Jönsson BA. Total plasma protein adducts of allergenic hexahydrophthalic and methylhexahydrophthalic anhydrides as biomarkers of long-term exposure. Scand J Work Environ Health. 2001;27(2):133-139. doi:10.5271/sjweh.600

4.Kanerva L, Hyry H, Jolanki R, Hytönen M, Estlander T. Delayed and immediate allergy caused by methylhexahydrophthalic anhydride. Contact Dermatitis. 1997;36(1):34-38. doi:10.1111/j.1600-0536.1997.tb00919.x

5.Yokota K, Johyama Y, Miyaue H, Matsumoto N, Yamaguchi K. Occupational contact urticaria caused by airborne methylhexahydrophthalic anhydride. Ind Health. 2001;39(4):347-352. doi:10.2486/indhealth.39.347